Knowledge of factors altering microvascular permeability is important for understanding fluid and solute exchange in the gastric mucosa in health and disease. Unfortunately, there is a dearth of studies concerning gastric mucosal microvascular permeability. Using a fluorescent in vivo microscopy technique, an injected fluorescein-albumin conjugate can be readily visualized circulating within the gastric microvessels and leaking out in response to various stimuli. The applicant has successfully applied this technique in studies of the effect of histamine and ethanol and proposes to continue and extend these studies. Paradoxically, prostaglandins, mediators of inflammation, protect the gastric mucosa against injury by a variety of agents. Employing in vivo microscopy, the applicant found that ethanol-induced gastric mucosal injury is accompanied by total stasis of blood flow in the injured area. Prostaglandin pretreatment protects against both the ethanol injury and the microcirculatory stasis. The first aim of this proposal is to determine the mechanism of this stasis and how prostaglandin prevents it. The hypothesis to be tested is that ethanol induces release of a venoconstricting agent, e.g. leukotriene C4, that results in constriction of submucosal venules and consequent mucosal microcirculatory stasis, markedly increases microvascular permeability with consequent severe hemoconcentration and stasis, and induces platelet thrombus formation. The second aim of the proposal is to study the effect of known mediators of inflammation on gastric mucosal microvascular permeability. The hypothesis to be tested is that bradykinin, serotonin and leukotriene, like histamine, will increase permeability, but prostaglandin E2 will not. In addition, the effect of oxygen-derived free radicals on gastric mucosal microvascular permeability will be studied, including their role in microvascular changes accompanying ischemic gastric mucosal injury. The third aim of the study is to determine the effect of vasoactive gut neuropeptides on mesenteric microvascular permeability. With the demonstration of a number of peptides in the nerves and endocrine cells of the gut wall, elucidation of their microvascular effects is important for determining their role in gastrointestinal physiology and pathophysiology.